1. Field of the Invention
The present invention relates to the use of superoxide dismutase (SOD), preferably of recombinant human SOD, in liposomes, for the preparation of pharmaceutical compositions, optionally mixed with hyaluronic acid and/or at least one physiologically acceptable carrier and/or other optional additives, for therapeutic and/or prophylactic use against increased concentrations of superoxide radicals and/or damage caused thereby.
2. Discussion of Related Art
Superoxide radicals are extremely reactive intermediate forms of the natural oxygen molecule and, as a result of this property, can irreversibly damage organic compounds in the cells of the human body. As protection from the dangerous effect of these superoxide radicals, the cells have an enzyme which is capable of rapidly converting such superoxide radicals into the more rapidly metabolizable and less toxic hydrogen peroxide (H.sub.2 O.sub.2). ##STR1##
Thereafter, the hydrogen peroxide, which is still toxic, is usually decomposed by the enzyme catalase into the harmless components water and oxygen. ##STR2##
The enzyme superoxide dismutase (SOD) occurs both in the human and animal body and in plants and presumably in all microorganisms which come directly into contact with atmospheric oxygen (aerobic bacteria and fungi). In the cells of higher organisms (eucaryotes), there are mainly two types of this SOD: a manganese-containing SOD which is localized in the mitochondria and is very similar to the bacterial SOD, and a second one which is present freely in the cytosol and contains copper and zinc atoms.
Unless stated otherwise, the term SOD is to be understood below as meaning mainly Cu,Zn--SOD, except for that from bovine blood erythrocytes, and bacterial or mitochondrial Mn--SOD and/or Fe--SOD, and recombinant human Cu,Zn--SOD (rhSOD).
Superoxide dismutase has been known under the name Orgotein since 1939, but the dismutase activity was not discovered and described until 1969, by McCord and Fridovich. Its practical use was limited in the past in particular by the short life or short biological availability of the protein under natural conditions, which of course has an adverse effect on the frequency of the dosage intervals, the therapeutic doses to be chosen and the associated costs.
The most investigated and used SOD to date was the Cu,Zn--SOD from bovine blood erythrocytes. Following severe and in some cases even fatal adverse reactions in the clinical-therapeutic use of bovine blood SOD, especially against arthritic diseases, preparations containing bovine blood SOD were prohibited, for example, in Austria. In particular, the preparation of recombinant human SOD, as described, for example, in AT 397 812 (Polymun Scientific, 1994), offers a way out of this situation.
Inter alia, the incorporation of SOD molecules in liposomes is a possible method for controlling the short life or short biological availability of the active substance SOD (Senga et al. 1990, Transplant. Proc. 22:2025).
The very first trial applications related to the treatment of inflammations and inflammatory processes of the skin. However, uses in osteoarthritis and rheumatic arthritis are now also reported in the literature (Hartmann et al. 1986, Proc. Natl. Acad. Sci. U.S.A. 83:7142; Bannister et al. 1987, Critical Rev. Biochem. 22:111). Especially in the area of medicine, it is also reported that SOD improves the storability of organs for the purpose of a subsequent transplantation (Olson et al. 1988, Transplant. Proc. 20:961), and a use for food preservation has already been mentioned (WO 85/01503).